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1
Lipid-Lowering Agents
Edward JN Ishac, Ph.D.
Department of Pharmacology and ToxicologyMedical College of VirginiaCampus of Virginia Commonwealth University Richmond, Virginia, USA
Smith Building, Room [email protected]
Agents used in HT, CHF, Arrhythmia and Angina
NO/cGMP, tolerance (off periods), flushing, dizziness, headache, reflex tachycardia, many forms
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aaNitrates
Effects enhanced in depolarized, damaged tissue, Phase 0, ↓ CV
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Na+-Channel blockers
Flushing, dizziness, headache, nausea, reflex tachycardia
aaaaaVasodilators
Many Rx interactions, [K+], ↓use HFimportant, low K+→↑toxicity,
aaaCardiac glycosides
GFR >30, hypokalemia (CG); ↑Ca++, diabetes (↓glucose tolerance)
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Diuretics (Thiazides)
Angioedema, hyperkalemia, cough (acei), tetrogenic, glossitis, taste
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ACEI / ARBs
HF, constipation, gingival hyperplasia, edema, reflex tachycardia
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Ca++-Channel blockers
HF (CI: unstable HF, broncho-spasm, significant bradycardia, depression); Raynaud D. Caution in diabetes, asthma (use β1-)
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Beta-Blockers
Contraindications/Cautions/Notes AnginaArrhythmia
HFHyper-tension
Drug Class
2
Leading Causes of Death in the U.S
0
250,000
500,000
750,000
1,000,000
Heart DiseaseCancerRespiratory Disease
AccidentsDiabetesInfluenzaAlzheimer's DiseaseData NIH 2000
Top Causes of Death (%), U.S.
1900 1983 2000
% T
op T
en C
ause
s of
Dea
th
DiabetesFlu/PneumoniaOther infectionsAccidentsCancerCardiovascular dsOther conditions
3
Relative Risk for CHD vs Total Cholesterol
Abbreviations and Definitions (Lipids)
TG [Triglyceride] VLDL, IDL, CM
FFA [Free Fatty Acids] TG, primary energy source
C [Cholesterol] VLDL, IDL, LDL, HDL, CM
CE [Cholesterol ester] VLDL, IDL, LDL, HDL, CM
4
Abbreviations and Definitions (Lipoproteins)
VLDL [very-low-density lipoprotein] [TG / CE] Apo B-100 [ATH]
IDL [intermediate-density lipoprotein] [TG / CE] Apo B-100 [ATH]
LDL [low-density lipoprotein] [TG / CE] Apo B-100 [very ATH]
HDL [high-density lipoprotein] [C / CE] Apo A, C, E [non-ATH]
CM [chylomicrons] [TG / CE] Apo B-48 [non-ATH]
Relative size, density and TG/Cholratio of different lipoproteins
Chylomicron
95% TG5% Chol
HDL
5% TG95% Chol
LDL
10% TG90% Chol
IDL
50% TG50% Chol
VLDL
80% TG20% Chol
TriglycerideCholesterol
5
Abbreviations and Definitions (Apoproteins)
CII apoprotein CII [lipoprotein lipase activator] [HDL]
A-1 apoprotein A-1 [LCAT cofactor] [HDL]
E apoprotein E [required for LP binding to receptors] [HDL]
B-48 apoprotein B-48 [structural apo for CMs]
B-100 apoprotein B-100 [structural apo for VLDL, IDL, LDL]
Abbreviations and Definitions (Enzymes)
LPL Lipoprotein [TG] Lipase TG ⇒ FFA [VLDL, CM]
HMG-CoA Reductase – Rate limiting step C synthesis
CETP Cholesterol ester transfer protein (HDL)
CE [HDL] exchanged for TG in lipoproteins
LCAT Lecithin:Cholesterol Acyltransferase (HDL)
takes up lipoprotein C and ⇒ CE for CETP
6
Atherosclerosis
Significance: Major cause of death in U. S.
Pathogenesis:
Injury/inflammation to blood vessel and infiltration of LDL and platelets. Formation of foam cells when LDL (oxidized) is internalized. Blood vessel is narrowed by plaque and blood clot reduces blood flow to brain (stroke) and heart (heart attack).
Pathogenesis of Atherosclerosis
Cell Injury Cell Proliferation Plaque Formation
7
Atherosclerosis: An Inflammatory Disease
III.2© 2002 PPS®
C
Atherosclerosis TimelineAtherosclerosis Timeline
FoamFoamCells Cells
FattyFattyStreak Streak
IntermediateIntermediateLesion Lesion
AtheromaAtheroma FibrousFibrousPlaquePlaque
ComplicatedComplicatedLesion/RuptureLesion/Rupture
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).
From FirstDecade
From ThirdDecade
From FourthDecade
Endothelial DysfunctionEndothelial Dysfunction
8
Coronary Occlusion
Surgical Treatment(Coronary bypass, angioplasty, stents)
9
Atherosclerosis
Risk Factors:
Hypertension age obesity
Diabetes high fat diet smoking
Stress low HDL lack of exercise
Family history High levels of VLDL, IDL and LDL.
Treatment: appropriate diet and drugs lowers mortality and morbidity 20 to 40%.
LDL Structure
TG, apo CII, E
AI & B48
10% TG; 90% C
10
Lipoprotein Metabolism I
Apo CII
& E on
HDL
Transfer
To CM & VLDL
⇑ CMs
⇑ CMRs
Intestine → CMs —[LPL] → CMRs → Liver [non-ATH]
Lipoprotein Metabolism
II
11
Factors Increasing HDL Levels
Exercise
Moderate Alcohol Intake
Weight Reduction (overweight)
Stop Smoking
Lipid-lowering drugs (Resins, Statins, Fibrates, Ezitimibe & Niacin)
Increased HDL levels are antiatherogenic
HDL enhances the clearance of LPs and Cholesterol
12
Not a Moderate Drink
Primary Hyperlipidemia (fasting blood sample)
Hypertriglyceridemia (TG 400-2,000 mg%) [PA= pro-atherosclerosis]1. Increased CMs (low LPL), non-atherogenic2. Increased CMs and VLDLs (low LPL & increased VLDL production) [PA]3. Increased VLDL (increased VLDL production and decreased LPL) [PA]4. Increased IDL & CM remnants (decreased clearance, low apo E) [PA]
Hypercholesterolemia (C 250-800 mg%)1. Increased VLDL and LDL (increased VLDL production) [PA]2. Increased LDL (increased LDL production and decreased LDL clearance) [↓ LDL receptors in genetic disorders, 50% heterozygote and 100% homozygote) [PA].
13
Secondary Hyperlipidemia
Hypertriglyceridemia (VLDL)Diabetes, oral contraceptives (estrogen), hypothyroidism, hypopituitarism, high sugar diet and high alcohol intake (increased production and decreased clearance of VLDL).
Hypercholesterolemia (LDL) High cholesterol (fat) diet, hypopitutarism and hypothyroidism (decreased LDL receptors).
Resins - MOAResins: Colestipol, Cholestyramine and Colesevelam1. Bind bile salts and block enterohepatic cycle of bile acids. 2. Lower cellular cholesterol content by increasing bile acid synthesis.3. Increase LDL receptors in liver.4. Rise in receptor-mediated endocytosis of LDL lowers plasma LDL levels.5. Increase in cholesterol biosynthesis (bad).6. Increase in plasma VLDL levels (bad) [do not use in patientswith elevated VLDL]7. Modest increase in HDL levels (10%) [good]
14
MAO of Resins and Statins
Cholestyramine ColestipolColesevelam
+ StatinsNormal
Beneficial Effects of Resins
Lower LDL levels about 15 to 25%
Increase HDL levels about 10%
Relatively safe drugs (no systemic absorption)
Good combo agents with statins
Decreases morbidity and mortality of CAD
15
Adverse Effects of Resins
Gritty bad taste, patients don’t like
Increase cellular cholesterol biosynthesis
Increase plasma VLDL levels ( do not use in patients with ⇑ VLDL, TGs).
GI: nausea, constipation, bloating (less with Colesevelam [Welchol])
Decreases absorption of other agents- fat soluble vitamins A, D, E & K- aspirin, thiazides, digoxin, phenobarbital
Statins - MOA
Statins : Fluvastatin, Rosuvastatin, Pravastatin, Lovastatin, Simvastatin and Atorvastatin. 1. Competitive inhibitors of HMG-CoA reductase which regulates cholesterol formation.2. Decreased cellular cholesterol level increases LDL receptors.3. Rise in receptor-mediated endocytosis of LDL lower plasma LDL levels. [15-50%]4. Modest increase in HDL levels (10%)5. Statins + Resins are good combination for lowering elevated LDL levels.6. Atorvastatin and simvastatin also lower VLDL.
16
MAO of Resins and Statins
Cholestyramine ColestipolColesevelam
+ StatinsNormal
Beneficial Effects of Statins
Lower plasma LDL levels, best agents (15 to 50%)
Increase plasma HDL levels (10%)
Atorvasatin & Simvastatin also lower plasma VLDL
ComboRx with Resins to lower plasma LDL
Reduce morbidity and mortality of CAD
17
Adverse Effects of StatinsMay produce headaches, rashes and myopathy (muscle damage)
May cause rhabdomyolysis (muscle wasting) and liver injury (higher doses). Monitor liver function
- alanine aminotransferase (ALT)- aspartate aminotransferase (AST)
Rhabdomyolysis potentiated with Gemfibrozil (avoid).
Caution: elderly, women (CI: pregnancy), children (<12), hypothyroidism, renal and liver dysfunction and drug interactions (reduced metabolism).
Statins – CYP450CYP450 3A4Inhibitors: Grape fruit, Erythromycin, Azithromycin, Dirithromycin, VerapamilGreat risk: Lovastatin, Simvastatin (x10-20)Moderate risk: Atorvastatin (x2-4)No risk: Fluvastatin, Pravastatin, Rosuvastatin
CYP450 2C9Inhibitors: Fluvastatin, (Simvastatin), Metronidazole, AmiodaroneGreat risk: Warfarin, Carvedilol (also 2D6), ARBs
18
Statin reduces heart attack, stroke rates in patients with normal cholesterol but elevated C-reactive protein (NEJM. Nov. 2008; Jupiter)• 17,802 patients (>89,000 patients screened) with
LDL "bad" cholesterol < 130 and high sensitivity C-reactive protein (hsCRP) greater than or equal to 2, given rosuvastatin (Crestor) over 1.9 years (4yr)
• 54% reduction of heart attacks• 48% reduction in stroke• 46% reduction for interventions (reopen vessels)• 20% reduction in all-cause mortality• no increase in either muscle pain or cancer • similar findings across gender, race and ethnicity
Potency of Statins
Statin dose required to lower LDL 30 to 35%
Atorvastatin [10 mg] = Rosuvastatin [10 mg] >
Simvastatin [20 mg] < Pravastatin [40 mg] =
Lovastatin [40 mg] < Fluvastatin [80 mg]
Atorvastatin and Rosuvastatin are most potent statins
Best if taken evenings with food
19
Ezetimibe - MOA
1. Inhibits cholesterol absorption in intestinal cells.2. Reduce cholesterol transport system in intestinal cell wall.3. Reduces cholesterol absorption by more than 50%.3. Reduces LDL by 18%.4. Reduces VLDL by about 5%.5. Increases HDL by about 3%.6. Ezetimibe enhances the lipid-lowering effects of statins.7**. In combination with statins enhances the reductions in LDL and VLDL. Less statin required to significantly lower LDL and VLDL (Now in question?).8. Dosage: 10 mg oral dose alone or combo with statins.
MAO of Resins, Statins & Ezetimibe
Cholestyramine+ Statins
+ EzetimibeNormal
20
Beneficial Effects of Ezetimibe
Reduces Plasma LDL (18%)
Reduces Plasma VLDL (5%)
Increases Plasma HDL (3%)
**Enhances the lipid-lowering effects of statins.
No adverse effects identified (safe drug??)
Clinical Trials
• SHARP (Study of Heart And Renal Protection)
• SEAS (Simvastatin and Ezetimibe in Aortic Stenosis)
• ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression)
• IMPROVE IT (Improved Reduction of Outcomes: VYTORIN Efficacy International Trial)
21
Clinical Studies• ENHANCE (Ezetimibe and Simvastatin in
Hypercholesterolemia Enhances Atherosclerosis Regression) Vytorin vs ZocorEndpoint plaque thickness, LDL ↓60%Vytorin ↑0.011 Zocor ↑0.005
• SHARP (Study of Heart And Renal Protection) 9,000 patients with chronic kidney disease. The study assesses the effect of Vytorin therapy on the time to the first major vascular event (i.e., heart attack, stroke, or revascularization)
Clinical Studies• SEAS (Simvastatin and Ezetimibe in Aortic
Stenosis): 1900, Reduction in mortality/morbidity of patients with heart valve stenosisVytorin ↑cancer 102/39 Placebo ↑67/23
• IMPROVE IT (Improved Reduction of Outcomes: VYTORIN Efficacy International Trial): 10,000, Evaluate risk reduction by VYTORIN vs Zocor(simvastatin) in reducing death and major coronary events in patients with acute coronary syndromes
22
Niacin (Nicotinic Acid and Vitamin B3 )
1. Decrease VLDL production by inhibiting adipose tissue lipolysis (main action).2. Increase VLDL clearance by increasing LPL activity.3. Lowers IDL and LDL production and content.4. Increases HDL levels (20-50%) best agent for increasing HDL.5. Lipoproteins: Lowers VLDL, IDL and LDLDose: 2-6 g oral dose given daily in divided doses (start low) with meals.
1. Resins2. Statins3. Niacin4. Fibrates5. Ezetimibe
Sites of
Action4
3
215
23
Beneficial Effects of Niacin
Lowers Plasma VLDL (primary), IDL and LDL.
Increases Plasma HDL (20 to 50%) [best HDL stimulator]
Reduces morbidity and mortality of CAD
Adverse Effects of Niacin
GI distress, facial and chest flushing (involves PG’s, reduced if aspirin taken just prior, now available as combo Rx), rashes and itching
Potentiates gout (decrease uric acid secretion), diabetes and peptic ulcers
May produce liver injury
24
Fibrates - MOAGemfibrozil, Fenofibrate, Clofibrate1. Increase VLDL (TG’s) clearance by increasing LPL activity
(best agent). Via activation of peroxisome proliferatoractivated receptor α (PPARα).
2. Decrease VLDL production by inhibiting adipose tissue lipolysis
3. Lowers IDL and LDL production and content.4. Increase HDL levels (20-30%).5. Lipoproteins: Lowers VLDL (TG’s), IDL and LDL.
Dosage: oral dose 1 to 2 times per day gemfibrozil (600 mg) fenofibrate (67 mg), fenofibrate is more potent than gemfibrozil.
Beneficial Effects of Gemfibrozil, Clofibrate & Fenofibrate
Lower Plasma VLDL (primary), IDL and LDL.
Greatest decrease in plasma TG’s (VLDL)
Increase Plasma HDL (20 to 30%)
Reduces morbidity and mortality of CAD
Fenofibrate is more potent than Gemfibrozil
25
Adverse Effects of Fibrates
GI distress (discomfort), rashes and headaches
May produce liver injury
Gemfibrozil potentiates myopathy with statins,combination should be avoided
Fenofibrate is safer to use with statins
May increase risk of gallstones
1. Resins2. Statins3. Niacin4. Fibrates5. Ezetimibe
Sites of
Action4
3
215
26
Lipid-Lowering Agents - Summary
Newest class: No major adverse effects noted
↑↓↓Inh. Cholesterol absorp.Ezetimibe
Nausea, skin rash, headache, ↑ statin myopathy, gallstones. ↑ LDL synthesis
↓↓↓↑↑↓FibratesLipoprotein lipase stim.Clofibrate, Gemfibrozil
Flushed face (↓aspirin), GI, glucose intolerance, gout, liver toxicity, ulcer, diabetes
↓↓↑↑↑↓↓Niacin(Nicotinic A. + Vit. B3)↓ VLDL release,↓ lipolysis in adipose
Liver toxicity, myopathy, ↓mylination CI: pregnancy, children. ↑↑ LDL-Rec
↓↑↓↓↓StatinsHMG-CoA reductase inhAtorvastatin, lovastatin
Hate it, gritty, GI discomfort, constipation, ↑ LDL-Rec., ↑VLDL, ↓ absp. fat sol. Vits.
↑↑↓↓Resins↓ Bile reabsorptionCholestyramine
NotesTGsHDLLDL
Adult Treatment Guidelines (2001)
> 200120-199< 120-150Triglycerides
> 60> 40> 50
HDL Cholesterol: MenWomen
Optimal <100mg/dl> 160130-159< 130LDL Cholesterol
High if >160mg/dl with coronary disease or more than 2 risk factors
> 240200-239< 200Total Cholesterol
NotesHighBorderline to high
Desirable mg/dl
Risk Factors: age > 45 (male) and 55 (females), family history of early vascular disease or hyperlipidemia, current cigarette smoker, elevated BP, obesity, diabetes and low HDL
27
Who Should Be Treated With Drugs?
LDL levels > 190 mg/dl and 0-1 risk factors.
LDL levels > 160 mg/dl and 2 or more risk factors.
CAD and LDL > 100 mg/dl.
Higher risk factors, more aggressive treatment
Risk Factors:
smoking obesity diabeteslow HDL family history of early CAD,hypertension age
Primary Hypertriglyceridedemia
↑ Lipoproteins Diet Drug Drugs
Chylomicrons low fat none noneno alcohol
Chylomicrons low fat, sugar Niacin none+ VLDL & alcohol, ↑PUFA Fibrates
VLDL low sugar & fat Niacin none↑PUFAs Fibrates none
IDL low fat, ↑PUFAs NiacinFibrates none
28
Primary Hypercholesterolemia
↑Lipoproteins Diet Drug Drug Combination
VLDL + LDL Low fat Fibrates Statins + EzetimibeNo Resins ↑PUFAs Statins Statins + NA/Fenfb
Niacin Stat + Ezet + NA/FB
LDL Low fat Resins Statins + Ezet/FenofNo Gemfibrozil ↑PUFAs Statins Resins + NA/Fenof/ with Statins Gemfibrozil
Niacin Resins + Statins andFibrates +NA/Fenofibrate
Quiz 1A 48-year-old man has a family history of
cardiovascular disease. Physical examination shows no abnormalities. Fasting serum lipid studies show:
Cholesterol total: 185 mg/dlLDL-cholesterol 140 mg/dlHDL-cholesterol 26 m/dl
Triglycerides 200 mg/dl
Which of the following agents is most appropriate?
A. CholestyramineB. EzetimibeC. GemfibrozilD. FluvastatinE. Niacin
29
Quiz 2A 48-year-old woman has no major medical illness but
a family history of cardiovascular disease. Fasting serum lipid studies show:
Cholesterol total: 180 mg/dlLDL-cholesterol 135 mg/dlHDL-cholesterol 30 m/dl
Triglycerides 245 mg/dl
Which of the following agents is most appropriate?
A. CholestyramineB. EzetimibeC. GemfibrozilD. SimvastatinE. Niacin
Quiz 3A 56-year-old woman comes to her physician because
of pain and cramps in her thighs for 2-weeks. Three months ago pharmacotherapy was initiated for dyslipidemia. Physical examination shows muscle tenderness in the thigh. Laboratory studies show elevated levels of aspartate aminotransferase (AST) and alanineaminotransferase (ALT).
Which of the following was the most likely agent prescribed to treat her dyslipidemia?
A. CholestyramineB. EzetimibeC. GemfibrozilD. SimvastatinE. Niacin
30
Quiz 4
A 46-year-old woman comes to her physician because of a 1-week history of a warm, tingling feeling over her face and chest. Two weeks ago pharmacotherapy was initiated for dyslipidemia.
Which of the following was the most likely agent prescribed to treat her dyslipidemia?
A. CholestyramineB. EzetimibeC. GemfibrozilD. SimvastatinE. Niacin
Quiz 5A 54-year-old woman has a family history of
cardiovascular disease. Fasting serum lipid studies show:Cholesterol total: 225 mg/dlLDL-cholesterol 180 mg/dlHDL-cholesterol 25 m/dl
Triglycerides 210 mg/dl
The physician commences pharmacotherapy with two agents to improve her lipid profile. Which drug combination is most appropriate for this patient?
A. Atorvastatin and CholestyramineB. Ezetimibe and AtorvastatinC. Niacin and AtorvastatinD. Niacin and CholestyramineE. Ezetimibe and CholestetyramineF. Ezetimibe and Niacin